This content is adapted from an ASCO Guidelines Podcast, published April 23, 2020, on the Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck. This conversation has been adapted for length and content.
The American Society of Clinical Oncology (ASCO) recently published a guideline on the Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck on its website. Guidelines help doctors choose the best treatments for people with cancer by providing up-to-date recommendations based on scientific evidence.
In this Q&A, guideline author Jessica Geiger, MD, discusses what squamous cell carcinoma of unknown primary in the head and neck is, what the new recommendations are for diagnosing and treating people with this diagnosis, and what this guideline means for patients. Dr. Geiger is a medical oncologist at the Taussig Cancer Institute at the Cleveland Clinic specializing in head and neck cancers.
Q: What is squamous cell carcinoma of unknown primary in the head and neck?
A: Cancer can start in many different kinds of cells. Squamous cell carcinoma begins in the flat squamous cells that make up the thin layer of tissue on the mucosal surfaces of the structures in the head and neck. Cancer of unknown primary in the head and neck is metastatic squamous cell carcinoma that is found in cervical lymph nodes located in the neck. Importantly in cancer of unknown primary, there's no primary mucosal tumor that's been identified. These patients comprise about 5% of all cases of head and neck cancers and pose a challenge for all members of the treatment team, both from a diagnostic perspective as well as treatment management. Because it is unclear exactly where the cancer began, the treatment team must ask themselves, what is the best way to proceed with these patients?
Q: What are the challenges in diagnosing squamous cell carcinoma of unknown primary in the head and neck?
A: The diagnostic challenges begin when a patient with a mass in the neck is being evaluated. They often have received imaging scans and a clinical exam. But in about 3% to 5% of patients, we will be unable to locate where this tumor started. Squamous cells don't show up in the lymph nodes by themselves; they came from somewhere else. Part of the reason that this makes it a diagnostic challenge is that we're not able to readily see where the primary tumor is. Oftentimes, the tumor is very small in size, so it's not picked up by imaging or by a physical exam. Also, these are sometimes difficult anatomic parts of the human body to evaluate. Together, all of this can pose a challenge to coming up with the correct diagnosis.
Q: What does ASCO recommend when diagnosing squamous cell carcinoma of unknown primary in the head and neck?
A: First and foremost, as always, we need to have a complete history and physical exam. This physical exam should include a fiberoptic laryngoscopy, which is a scope exam visualizing all of the mucosal tissue, trying to find abnormalities and to see where exactly this cancer started.
In order to diagnose squamous cell carcinoma, a biopsy is performed in the neck. Either a fine needle aspiration or a core needle biopsy is recommended within these guidelines. The guidelines also indicate when to do additional pathologic testing. This additional testing is to look for high-risk human papillomavirus (HPV), especially in lymph nodes that are in the middle of the neck, or testing for Epstein-Barr virus (EBV), as this may indicate a potential nasopharyngeal cancer. With this additional testing, we are trying to determine possible primary location: oropharynx with HPV testing, for example, or nasopharnx primary with EBV testing.
Then we have imaging guidelines. The preferred choice is a CT scan of the neck using contrast medium, not just to better evaluate the number and location of the lymph nodes but also to look for evidence of the primary tumor. If that fails to find a primary tumor, then we give recommendations regarding PET scans.
Q: What does ASCO recommend for surgery for squamous cell carcinoma of unknown primary in the head and neck?
A: First, as part of diagnosis, all patients need a complete surgical evaluation of the upper aerodigestive path. The surgeon is able to better visualize all tissues and samples are taken from any places where there is suspicion of possible cancer.
The recommendations for surgery also include when to do tonsillectomies and what tonsillectomies to do. The recommendations are based on how much cancer has spread to the lymph nodes. Is there cancer in lymph nodes on both sides of the neck? Or on just one side? How big are the nodes? Is there a concern that there is cancer extending outside of the capsule of the lymph nodes? That all plays a role in the recommendations regarding surgical diagnostics or intervention.
If a primary tumor is identified and a therapeutic surgery is planned, there are clear recommendations and guidelines to make every effort to remove the tumor with negative margins; this means no cancer cells are found at the edge of the removed tumor. The reason we want to stress that negative margins are the goal is because we're trying to avoid having to use 3 types of treatment, which is called trimodal therapy. If surgery leaves a positive margin, that is likely going to lead to recommendations for radiation therapy plus chemotherapy. We want to try to avoid the side effects that come with trimodal therapy.
Recommendations for neck surgery are divided into whether there is small-volume disease or large-volume disease. For unilateral or bilateral small-volume neck disease, or small lymph nodes on either 1 or both sides of the neck, we recommend a multidisciplinary discussion among the health care team about whether surgery involving a neck dissection or radiation therapy is best. Again, our primary goal is to adequately treat with the fewest types of treatment possible in order to minimize unwanted side effects of combined treatment plans. For large-volume neck disease on both sides of the neck, or when we suspect tumor spillage outside of the confines of the node capsule, combined chemotherapy and radiation therapy is preferred; this is called chemoradiotherapy.
Q: What does ASCO recommend for radiation therapy?
A: If a patient is receiving radiation therapy as the primary treatment for cancer of unknown primary, we recommend that radiation therapy should be directed to involved lymph nodes and also to parts of the head and neck that are considered at risk for containing microscopic cancer cells. So, it's not just good enough to radiate what we see on imaging but also areas at risk for microscopic spread, which means cancer may be present but we cannot see it on imaging or exam.
Also included within the radiation therapy guidelines are recommendations regarding volumes and doses. What doses do you use? Where do you use these doses? These doses are extrapolated from well-established scientific evidence for traditional head and neck squamous cell carcinoma in which we know where the primary tumor is.
Q: What does ASCO recommend for systemic therapy using medication?
A: When it comes to treating cancer with medications, we recommend adding chemotherapy to radiation therapy in order to increase the effects of radiation therapy in cases of large-volume nodal disease, which can be a single large node more than 3 centimeters, multiple metastatic lymph nodes, and/or cancer spreading out of the confines of the node capsule into surrounding soft tissues.
There are also recommendations regarding cancer of unknown primary that’s been treated with surgery. If there is evidence that the cancer has grown outside of the lymph nodes and into the tissue that surrounds it, called extracapsular extension, we recommend adding chemotherapy to radiation therapy after surgery.
If your doctor is concerned that this is an Epstein-Barr-related nasopharyngeal cancer, stages 2 through 4A, we recommend adding chemotherapy to radiation therapy in those settings as well. The chemotherapy that ASCO recommends is cisplatin (available as a generic drug). Again, this is based on well-established studies and scientific evidence in head and neck cancer.
Q: How will these guideline recommendations affect patients?
A: This guideline is important because a fair number of patients present with cancer of unknown primary, and standardized guidance is needed for people with this diagnosis. These are evidence-based recommendations and guidelines that focus on a multidisciplinary approach to give these patients the best treatment possible.
Hopefully this guideline will provide reassurance to patients that no matter where they are receiving treatment, they are receiving quality standard-of-care management. It shouldn’t matter where they are being treated or by whom; they're being treated by the standard of care that is accepted across the oncology profession and has a track record supported by scientific evidence.